Immune Pathogenesis of Psoriasis: Role of Biologic Therapies
These are very exciting times for dermatology. Basic research is being applied to the development of new and more effective biologics to treat some of the most challenging conditions, psoriasis among them.
Table 1. Nomenclature of selected classes of biologic therapies
Although psoriasis is now considered a T-cell–mediated autoimmune disease, descriptions of the cutaneous immune response have been based primarily on observations of allergic contact dermatitis. The key players-T cells, Langerhans' cells, keratinocytes, and blood vessels-interact with T-cell receptors and various accessory molecules to produce the cutaneous immune response. One of the important initial events involves activation of Langerhans' cells. In order for a Langerhans' cell to present antigen to a T cell, it must migrate from its resident position in the skin to the regional lymph node, then act on the T-cell/antigen-presenting–cell interaction via various adhesion molecules. Interference with the movement of Langerhans' cells in a T-cell/Langerhans' cell-mediated immune response could, therefore, blunt an inflammatory response.
Table 2. Selected biologic therapies in development for psoriasis (drugs listed in order of the phase of development)
In the late 1990s, tumor necrosis factor (TNF) type 2 receptor was identified as a crucial player in Langerhans' cell migration, and animal studies showed that knocking out that receptor dramatically reduced contact hypersensitivity. The balance between the primary cytokines TNF and interleukin-1 (IL-1)-which signal either anti-inflammatory or proinflammatory secondary cytokines-determines whether a response will be a robust inflammatory response or a blunted response. Inhibiting these cytokines (TNF and IL-1) can dramatically reduce and blunt the inflammatory response. T-lymphocyte cytokine profiles can be categorized as T1 and T2. T1 diseases include psoriasis, allergic dermatitis, cutaneous T-cell lymphoma, tuberculoid leprosy, and granulomatous skin disease. T2 diseases include atopic dermatitis, Sezary syndrome, and lepromatous leprosy.
Figure 1. Key actions of TNF-a in psoriasis
Activated T cells play an important role in the pathogenesis of psoriasis. These cells, which can trigger keratinocytes to develop into psoriasis plaques, are the target of drugs that suppress T-cell activation. The drugs work at blocking various steps in the process, from T-cell activation in the lymph nodes, to T-cell binding and trafficking into the dermis and epidermis, to secondary activation (reactivation) of T cells in the dermis and epidermis.
Immune modulatory drugs in psoriasis have been classified according to the part of the pathogenetic process they target. Classification of biologics is further clarified by an understanding of the nomenclature (Table 1). Selected biologic therapies in development for psoriasis are listed according to the part of the process they target (Table 2).
Figure 2. Etanercept phase 2 results: plaque thickness
An Example of a Biologic Strategy
Etanercept and infliximab are TNF inhibitors that exemplify Strategies 1 and 5. In Strategy 1, they inhibit keratinocyte primary cytokines and Langerhans' cell migration. In Strategy 5 they bind postsecretory cytokines. TNF is prominent in psoriatic arthritis and psoriasis-it is present in active plaques, with higher bioactivity in involved skin compared to uninvolved skin. Serum and synovial TNF levels are elevated in affected patients and fluctuate with disease activity. TNF-a is important in the initial cytokine cascade and in keratinocyte activation inducing Langerhans' cell migration. The key actions of TNF-a are shown in Figure 1. TNF also is capable of activating T lymphocytes, activating endothelium to express vascular endothelial growth factor, and activating keratinocytes for proliferation responses.
Figure 3. Etanercept phase 2 results: epidermal T-cell infiltration
Etanercept is a soluble TNF receptor, made from soluble human TNF receptors, that competitively binds circulating TNF, making it unavailable for activation of cell-surface receptors. Infliximab is a chimeric monoclonal antibody, including murine variable regions and human IgG1 constant regions, that specifically inhibits TNF-a.
Phase 2 studies have resulted in promising data. Infliximab 5 mg/kg was associated with a significant decrease in Psoriasis Area and Severity Index (PASI). Etanercept produced a 44% mean decrease in epidermal thickness at week 12 (Figure 2), a 69% decrease in epidermal T-cell infiltration at week 12 (Figure 3), and dramatic decreases in PASI after 24 weeks of treatment (Figure 4).
Figure 4. Etanercept phase 2 clinical response
The discovery that a disease such as psoriasis can be a prototype of T-cell–mediated immunity has led to significant advances in our understanding of the molecular basis of inflammatory skin diseases. Disruption of signaling pathways and cytokine cascades that occur in inflammatory diseases can have a dramatic effect on the pathogenesis of disease. Modification of these pathways by specific agonists and antagonists is leading to specific and effective therapeutic interventions.
MORE ARTICLES IN THIS ISSUE
TNF Inhibitors: Potential for Use in Dermatology Practice
Psoriasis is a chronic inflammatory disease characterized by well-demarcated red, raised, scaly lesions on any part of the body. The disease often severely impacts patients' mental and physical functioning and quality of life. Signs and symptoms may vary from mild to generalized cutaneous involvement, with or without associated joint disease.
Long-term Safety and Tolerability Experience with TNF Inhibitors
The class of agents known as TNF inhibitors shares some common safety issues, but the safety profiles of specific agents vary due to differing characteristics and mechanisms. Comparing safety data of these drugs is, of course, complicated by differences in patient populations and experiences.
Advances in Biotherapy: The Pivotal Role of TNF Inhibition in Psoriatic Arthritis and Psoriasis (PDF)
A CME monograph sponsored by The Institute for Medical Studies and Advanstar Healthcare Communications. Supported by an unrestricted educational grant from Amgen Inc. and Wyeth Pharmaceuticals.
The views and opinions expressed are those of the interviewed physicians and do not necessarily reflect the views of the editors, Advanstar Healthcare Communications. The Institute of Medical Studies, Amgen Inc., or Wyeth Pharmaceuticals. For faculty, and learning objectives please download this PDF file.
Use of TNF Inhibitors: The Changing Treatment Paradigm
Current therapies for psoriasis can be very effective and are acceptable to many patients. However, a number of drawbacks associated with these treatments may compromise their effectiveness. Patients undergoing ultraviolet B (UVB) phototherapy or psoralen plus ultraviolet A (PUVA) treatments must keep their appointments 3 times a week to maintain the effectiveness of the therapy.